chr7-117559629-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM5PP2BP4_Strong
The NM_000492.4(CFTR):c.1558G>A(p.Val520Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,613,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V520F) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1558G>A | p.Val520Ile | missense_variant | Exon 11 of 27 | ENST00000003084.11 | NP_000483.3 | |
| CFTR-AS1 | NR_149084.1 | n.221+1104C>T | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000237 AC: 36AN: 152038Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000147 AC: 37AN: 251102 AF XY: 0.0000810 show subpopulations
GnomAD4 exome AF: 0.000101 AC: 148AN: 1460978Hom.: 0 Cov.: 30 AF XY: 0.0000784 AC XY: 57AN XY: 726852 show subpopulations
GnomAD4 genome 0.000237 AC: 36AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74390 show subpopulations
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:6Benign:1
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 520 of the CFTR protein (p.Val520Ile). This variant is present in population databases (rs77646904, gnomAD 0.08%). This missense change has been observed in individuals with congenital absence of vas deferens and/or cystic fibrosis (PMID: 12167682, 14998948, 16596947, 17020473, 19324992, 30811104). ClinVar contains an entry for this variant (Variation ID: 35825). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Val520 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23891399, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:6
Observed in individuals with CFTR-related disorders (PMID: 14998948, 29997923, 30811104, 32777524); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26708955, 25735457, 18937943, 25087612, 29997923, 12167682, 29216686, 16596947, 17020473, 19324992, 23974870, 14998948, 24517344, 34426522, 32366966, 34996830, 30811104, 32777524, 35913788, 38388235, 38933898, 36193559) -
CFTR: PM5, BP2 -
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The CFTR c.1558G>A; p.Val520Ile variant (rs77646904) has been reported in the literature in individuals with mild or atypical cystic fibrosis, including in individuals with congenital bilateral absence of the vas deferens (Bienvenue 2005, Danziger 2004, Groman 2002, Guan 2018, Schwartz 2009, Yuan 2019), but in many cases a second CFTR variant was not identified. Additionally, another variant in the same codon, p.Val520Phe, is a known pathogenic variant (Sosnay 2013). The p.Val520Ile variant is reported in ClinVar (Variation ID: 35825) and is found in general population with an overall allele frequency of 0.015% (43/282480 alleles) in the Genome Aggregation Database. The valine at codon 520 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.486). Due to limited information, the clinical significance of the p.Val520Ile variant is uncertain at this time. References: Bienvenu T et al. Spectrum of CFTR mutations on Reunion Island: impact on neonatal screening. Hum Biol. 2005. 77(5):705-14. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004. 19(3):540-6. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002. 347(6):401-7. Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. Schwartz K et al. Identification of cystic fibrosis variants by polymerase chain reaction/oligonucleotide ligation assay. J Mol Diagn. 2009. 11(3):211-5. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. 45(10):1160-7. Yuan P et al. Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles. Andrology. 2019 May;7(3):329-340. -
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The CFTR c.1558G>A (p.Val520Ile) variant has been reported in the published literature in individuals with cystic fibrosis and/or congenital absence of the vas deferens (PMIDs: 32777524 (2021), 30811104 (2019), 19324992 (2009), 14998948 (2004), and 12167682 (2002)), as well as bronchiectasis (PMID: 29997923 (2018)). The frequency of this variant in the general population, 0.001 (20/19950 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
CFTR-related disorder Uncertain:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
The CFTR c.1558G>A variant is predicted to result in the amino acid substitution p.Val520Ile. This variant has been reported in individuals affected with CFTR-related disorders including cystic fibrosis (Bienvenu et al. 2005. PubMed ID: 16596947), non-classic cystic fibrosis (Groman et al. 2002. PubMed ID: 12167682), congenital bilateral absence of the vas deferens (Danziger et al. 2004. PubMed ID: 14998948; Yuan et al. 2019. PubMed ID: 30811104), and bronchitis (Nectoux et al. 2006. PubMed ID: 17020473). However, a second pathogenic CFTR variant was not identified or specified in these patients. This variant was also identified in the heterozygous state in an individual of unknown phenotype undergoing either diagnostic or carrier testing in the CFTR gene (Schwartz et al. 2009. PubMed ID: 19324992). An alternative nucleotide substitution resulting in a different missense change at the same amino acid position (p.Val520Phe) has been reported as causative for cystic fibrosis (Sosnay et al. 2013. PubMed ID: 23974870, Van Goor et al. 2014. PubMed ID: 23891399). However, at this time, the clinical significance of the c.1558G>A (p.Val520Ile) variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary pancreatitis Uncertain:2
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not specified Uncertain:1
Variant summary: CFTR c.1558G>A (p.Val520Ile) results in a conservative amino acid change located in the AAA+ ATPase domain and ABC transporter-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251302 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00015 vs 0.013), allowing no conclusion about variant significance. c.1558G>A has been reported in the literature in individuals affected with Cystic Fibrosis or CFTR-related disorders (e.g. CBAVD, bronchiectasis) (e.g. Bienvenu_2005, Danziger_2004, Guan_2018, Nectoux_2006, Yuan_2019, Luo_2021) and also other phenotypes such as lung adenocarcinoma, non-obstructive azoospermia or severe oligozoospermia and pancreatic cancer (e.g. Donner_2018, Oud_2017, Tamura_2018, Smits_2019). In further detail, the variant was seen in a CF patient with a mild disease who had no other CFTR mutations (Nectoux_2006) and in an Indian CF patient who had an unknown mutation on his other CF chromosome (Sick Kids database). In addition, the variant was observed in a CF patient who also carried 2347delG and deltaF508 mutations (Bienvenu_2005). These co-occurrences indicate that the variant may be in the benign spectrum. Furthermore, c.1558G>A has been documented in CBAVD patients who were reported to also carry 3601-3C>A (c.3469-3C>A as per HGVS nomenclature) (Danziger_2004) and c.2042A>T (Yuan_2019). Claustres et al (2017) report the variant in trans with p.K710X being observed in an asymptomatic compound heterozygote individual. Taken together, these reports do not allow for unequivocal conclusions about association of the variant with cystic fibrosis. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1558G>T, p.Val520Phe), supporting the critical relevance of codon 520 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately ~41% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 12167682, 17020473, 16596947, 14998948, 24517344, 25087612, 25735457, 18937943, 26708955, 28603918, 28801929, 29997923, 29669919, 30032850, 30811104, 31672438, 32777524, 34996830, 38388235). ClinVar contains an entry for this variant (Variation ID: 35825). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at